This R34 grant proposal is to plan a clinical trial that will test the proof-of-concept that two candidate hookworm vaccine antigens, Na-GST-1 and Na-APR-1 (M74), can have a biological impact on hookworm infection. This trial will utilize a new paradigm for early assessment of new vaccine antigens by challenging human volunteers with a controlled experimental hookworm infection after vaccination. Hookworm is one of the most important parasitic infections, with over 500 million people infected worldwide, most with the Necator americanus species. The clinical hallmark of hookworm infection is iron deficiency anemia resulting from intestinal blood loss. Both Na-GST-1 and Na-APR-1 are components of the blood-feeding pathway of N. americanus and were selected for clinical development based on their protective efficacy in animal trials. The clinical development plan is to eventually combine the two antigens into a single, bivalent vaccine product. Recombinant Na-GST-1 and Na-APR-1 (M74), both formulated on Alhydrogel(r), have been shown to be safe when administered to healthy adults in Phase 1 trials. In the proposed study, healthy hookworm-nave adult volunteers will be vaccinated followed by challenging them with infective N. americanus larvae to assess the effect of vaccination on infection, as assessed by parasitologic, immunologic and hematologic parameters. Traditionally, proof-of-concept for novel investigational vaccines is tested in large field trials in endemic areas. These can take considerable time depending on the incidence of infection in the control arm of the study. The objective of this R34 proposal is to plan a study in which proof-of-concept is tested early in the clinical development of new vaccines for hookworm, one of the most prevalent and important of the Neglected Tropical Diseases. The results of this trial will permit critical Go/NoGo decisions to be made on further development of the Na-GST-1 and Na-APR-1 (M74) hookworm vaccine, prior to conducting larger, more costly Phase 2 and 3 trials.